WO2024043661A1 - Ionic bond compound of pelubiprofen and tramadol, composition including same, and preparation method therefor - Google Patents

Abstract

Provided are an ionic bond compound of pelubiprofen and tramadol, a composition including same, and a preparation method therefor.

Description

Ionic compound of felubiprofen and tramadol, composition containing the same, and method for producing the same

It relates to a novel compound in which felubiprofen and tramadol are ionically bonded, a composition containing the same, and a method for producing the same.

Felubiprofen is a type of non-steroidal anti-inflammatory drug (NSAID) and has pharmacological anti-inflammatory, analgesic, and antipyretic effects. NSAID drugs such as felubiprofen inhibit the function of cyclooxygenase (COX), which is required to synthesize prostaglandin (PG), thereby dulling the sensation caused by pain by regulating inflammatory responses and inflammatory mediators. NSAID side effects are mainly caused by inhibition of COX-1, which is responsible for maintaining homeostasis such as protecting the gastrointestinal mucosa, maintaining renal blood flow, and regulating platelet activity. However, if COX-2 is inhibited, cardiovascular side effects also occur, so COX-1 and COX- It is necessary to adjust 2 to an appropriate ratio. Felubiprofen is known to regulate COX-1 and COX-2 in an appropriate ratio of about 3:7.

Tramadol is an opioid analgesic that acts on the central nervous system and has been mainly used for severe and severe acute and chronic pain. It is a non-narcotic analgesic. Tramadol exerts analgesic effects through two mechanisms: one is a non-narcotic action that stimulates the secretion of serotonin and suppresses pain by inhibiting the reuptake of norepinephrine and serotonin, and the other is mu (μ), one of the opioid receptors. ) It acts on receptors to suppress pain. Side effects that may occur when tramadol is taken long-term or in high doses include serotonin syndrome, which is caused by increased serotonin concentration. The main symptoms of serotonin syndrome are tremors, seizures, muscle stiffness, and neuromuscular problems that make it difficult to maintain a proper posture. Symptom; High fever and mental symptoms such as anxiety and agitation; Symptoms of dysautonomia include blood pressure fluctuations, tachycardia, sweating, diarrhea, and nausea. Other side effects that may occur when tramadol is taken long-term or in high doses include symptoms related to opioid receptors, such as drowsiness, dizziness, lethargy, confusion, and insomnia.

In 2001, tablets (Ultracet, Janssen) containing acetaminophen and tramadol hydrochloride as active ingredients were developed to compensate for the short duration of effect of acetaminophen and the side effects caused by high doses of tramadol. However, the hepatotoxicity of acetaminophen and the side effects of tramadol were developed. Not only does the problem of other side effects still exist, but it is only a simple combination of acetaminophen and tramadol hydrochloride, and does not disclose a single compound in which the two active ingredients are ionically bonded, such as the ionic bond compound of felubiprofen and tramadol.

International Publication WO2011-015360 relates to a salt of desmethyl-tramadol and a COX inhibitor, but does not disclose specific preparation examples for a compound combined with felubiprofen. Desmethyl-tramadol is an active metabolite of tramadol and is structurally different from tramadol in that the methoxy group of tramadol is changed to a hydroxy group. This structural difference affects ionic bonding, making it difficult to produce ionic compounds.

Korean Patent Publication No. 10-2013-0129070 relates to salts of diclofenac and tramadol, but does not disclose ionic compounds of felubiprofen and tramadol. Unlike diclofenac, which has a phenylacetic acid group, felubiprofen is not only structurally different in that it has a 2-phenylpropanoic acid group, but is also a different compound with different charges, so it is difficult to predict whether an ionic bond will be formed. Moreover, as the size of each molecule increases, it becomes difficult to form ionic bonds due to steric hindrance. Pelubiprofen forms ionic bonds more difficult than diclofenac because the methyl group is close to the carboxylic acid group that forms ionic bonds, forming steric hindrance.

Meanwhile, tramadol is used in the form of tramadol hydrochloride due to the instability of the free base form. Tramadol hydrochloride shows high water solubility, but felubiprofen is a poorly soluble drug with low water solubility, so it is a drug that can exhibit the effects of both pharmacologically active ingredients. There are many difficulties in the development of . Surprisingly, the present inventors completed the present invention by manufacturing felubiprofen with tramadol and an ionic compound, thereby developing a pharmaceutical that exhibits the effects of both pharmacologically active ingredients while improving physicochemical stability.

One aspect is to provide a novel ionic compound with improved physicochemical properties by combining felubiprofen and tramadol by a non-covalent bond.

Another aspect is to provide a pharmaceutical composition for treating pain containing an ionic compound of felubiprofen and tramadol as an active ingredient.

Another aspect is to provide a method for producing the ionic compound of felubiprofen and tramadol.

One aspect provides an ionic compound of felubiprofen and tramadol.

In one embodiment, felubiprofen and tramadol are combined in a molar ratio of 1:1.

Another aspect provides a pharmaceutical composition for treating pain containing an ionic compound of felubiprofen and tramadol as an active ingredient.

In one embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, diluents, binders, lubricants, and any combinations thereof.

Another aspect provides a method for producing the ion-binding compound of felubiprofen and tramadol.

In one embodiment, the manufacturing method is

Step (1) of dissolving trimadol free base to obtain a dissolved product; and

Obtaining a solid reactant by adding felubiprofen to the melt (2); Includes.

In one embodiment, in step (1), trimadol free base is obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, which is washed, dried, and filtered.

Other objects and advantages of the present application will become clearer from the claims and description of the invention. Contents not described in this specification can be fully recognized and inferred by a person skilled in the technical field of this application or a similar technical field, so description thereof is omitted.

The novel ionic compound of felubiprofen and tramadol of the present invention is a compound in which two pharmacologically active ingredients are combined at a constant stoichiometric ratio, and has improved physical properties in terms of dissolution rate, hygroscopicity, and stability compared to a physical mixture of the two ingredients. It has chemical properties. In addition, the compound of the present invention has various advantages in terms of formulation and production compared to a physical mixture of two components, and has an economic advantage in that the process of formulating a single compound is overall simpler and easier than formulating two types of compounds. to provide.

Figure 1 shows the results of measuring Fourier transform IR spectra for felubiprofen and tramadol ionic compounds (felubiprofen and tramadol salts), tramadol free base, tramadol hydrochloride, and felubiprofen.

Figure 2 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high temperature (80 ± 1°C) conditions.

Figure 3 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high humidity (90 ± 1%) conditions.

Hereinafter, the present invention will be described in more detail.

All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art in the field related to the present invention. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention. The contents of all publications incorporated by reference herein are hereby incorporated by reference in their entirety.

The term “ionic bond” used in this specification is a cohesive bond that occurs when cations and anions are combined by electrostatic attraction. More specifically, an ionic bond refers to a type of chemical bond in which one or more electrons are completely transferred from one atom to another, changing a neutral atom into a charged ion, and positive and negative ions are bonded through electrostatic attraction.

The term "ionic bonding compound" used in this specification refers to a compound formed by ionic bonding and is composed of ions with opposite charges due to electrostatic force in a sequential arrangement through ionic bonding. Also referred to as “ionic compound”. Preferably, the ionic bonding compound according to the present invention refers to a single compound in which the ions of two or more active drug molecules are bonded through an ionic bond.

The ionic compound according to the present invention is distinguished from a co-crystal in that it is a bond of ions with opposite charges, which is a weak bond, for example, a nonionic bond or noncovalent bond between molecules. , It is also distinguished from co-crystals, which contain inactive molecules, that is, coformers, among the molecules constituting the crystal.

“Pelubiprofen” means (±)-(E)-2-[4-(2-(oxo-cyclohexylidenemethyl)-phenyl]propionic acid ((±)-(E)-2- [4-(2-(Oxo-cyclohexylidenemethyl)-phenyl] propionic acid) refers to the common name of the compound. Felubiprofen is a poorly soluble drug and has a water solubility of approximately 0.092 mg/mL.

“Tramadol” is the compound 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol. Refers to the common name. The water solubility of tramadol is about 0.75 mg/mL, and the water solubility of tramadol hydrochloride is about 100-1000 mg/mL (freely soluble).

The compound of felubiprofen and tramadol according to one embodiment of the present invention is a solid state material in which felubiprofen and tramadol are bonded, preferably by a non-covalent bond, and more preferably by an ion formed by an ionic bond. It is a binding compound.

Solid-state substances composed of two or more molecules can be manufactured in the form of co-crystals, solvates, hydrates, salts, etc., depending on the properties of the molecular compound. Generally, ionic bonds are formed when there is a large difference in electronegativity between two elements, for example between a metal and a non-metal or between non-metallic substances.

In a preferred embodiment, the compound according to the present invention is an ionic compound prepared in the form of a salt. The compound prepared in the form of a salt has each component arranged based on ion-pairing and is formed through an acid-base reaction by proton transfer from an acid to a base. The compound according to one embodiment of the present invention is an ionic compound prepared in salt form through an acid-base reaction in which a proton is transferred from felubiprofen to tramadol.

The compound of felubiprofen and tramadol according to one embodiment of the present invention is different from general salt compounds or ionic compounds in that the two pharmacologically active ingredients are bonded by an ionic bond.

Moreover, multi-drug ionic bond compounds, such as the compound according to one embodiment of the present invention, are more difficult to manufacture than general salt compounds due to the chemical structure, charge difference, and steric hindrance of the molecular compound forming the ionic bond, and are actually manufactured. Without this, it is difficult to predict the formation of ionic bonds and the molecular structure of the compound.

In addition, in the compound according to one embodiment of the present invention, two different pharmacologically active ingredients are combined by an ionic bond to form one compound, and therefore, two or more pharmacologically active ingredients exist simply as a physically mixed mixture. It is clearly distinguished from the combination drug. For example, in a combination drug, two different drug molecules are mixed without forming a specific bond, whereas in the compound according to one embodiment of the present invention, two different pharmacologically active ingredients are mixed with a specific bond, preferably a non-covalent bond. , more preferably, to form an ionic bond to form one compound.

More specifically, the ionic binding compound of felubiprofen and tramadol according to one embodiment of the present invention is that the two active pharmaceutical ingredients (API), felubiprofen and tramadol, are in ionic form with opposite charges, that is, , felubiprofen anion and tramadol cation combine to form a salt.

In one embodiment, the ionic compound is a compound in which two different drug molecules are combined at a constant stoichiometric ratio. In one embodiment, felubiprofen and tramadol are combined in a molar ratio of 1:1.

In the ion-binding compound of felubiprofen and tramadol according to one embodiment of the present invention, the two pharmacologically active ingredients act as one compound during the manufacturing process of the drug or before taking the drug, but reach the pharmacologically active site after taking the drug. Before doing so, each pharmacologically active ingredient can be substantially separated in the body to exhibit its respective medicinal effects.

In the ionic-binding compound according to one embodiment of the present invention, two or more pharmacologically active ingredients behave as one compound during the manufacturing process, so problems that may arise when simply mixing them and manufacturing them in a solid form such as tablets, for example, each ingredient Distribution unevenness can be resolved.

Moreover, due to the low physicochemical stability of felubiprofen and tramadol, it is difficult to ensure quality stability of the drug when manufactured as a simple mixture. For example, when felubiprofen and tramadol hydrochloride are simply mixed and stored under high temperature conditions for a long period of time, the color changes to dark yellow, and when stored under high humidity conditions, it is obtained in a liquid or sticky form (see Experimental Example 3). In one embodiment of the present invention, this physicochemical instability was solved by providing a new compound in which felubiprofen and tramadol are ionically bonded.

In addition, the ionic compound of felubiprofen and tramadol according to an embodiment of the present invention shows improvements in physicochemical properties such as stability, hygroscopicity, solubility, and dissolution rate compared to a mixture in which each pharmacologically active substance is simply mixed. Because of these improved physicochemical properties, the compounds of the present invention offer a variety of unexpected advantages in pharmaceutical formulation over physical mixtures. In addition, it provides an economic advantage in that the process of formulating a single compound is overall simpler and easier compared to formulating two types of drugs.

Another aspect provides a pharmaceutical composition for treating pain containing an ionic compound of felubiprofen and tramadol as an active ingredient.

In one embodiment, the pharmaceutical composition may include a therapeutically effective amount of the ionic compound of felubiprofen and tramadol.

In one embodiment, the pharmaceutical composition may be formulated for oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration.

In one embodiment, the pharmaceutical composition may further include one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, diluents, binders, lubricants, and any combinations thereof. The excipient is any substance known to those skilled in the art to be useful in preparing the formulation, and its components and content can be adjusted as needed, for example, depending on the form to be formulated or the mode of administration of the drug.

Another aspect provides the use of felubiprofen and tramadol ionic compounds in the treatment of pain.

Another aspect provides a method of treating pain comprising administering to a subject an ionic compound of felubiprofen and tramadol.

In one embodiment, the dosage of the ionic-binding compound or a pharmaceutical composition containing the same is an amount effective for the purpose of treating pain in the subject, including the subject's weight, age, gender, health condition, diet, administration time, administration method, and disease. The dose can be adjusted appropriately by an expert, taking into account various related factors such as the severity of the disease.

In one embodiment, treating pain includes reducing, suppressing, eliminating, ameliorating or preventing pain.

As used herein, the term “treatment” refers to inhibiting a disease, condition or disorder in a subject experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder, i.e. preventing further development of the pathology and/or symptoms, or Ameliorating a disease, e.g. ameliorating a disease, condition or disorder in a subject experiencing or exhibiting pathology or signs of the disease, condition or disorder, i.e. reversing the pathology and/or signs, e.g. disease severity This means reducing.

As used herein, the term “prophylaxis” refers to preventing a disease, e.g., preventing a disease, condition or disorder in a subject who may be predisposed to the disease, condition or disorder but has not yet experienced or exhibited symptoms or pathology of the disease. It says what to do.

As used herein, the term "subject", "individual", or "patient" refers to a living mammalian organism, such as a primate, human, monkey, cow, sheep, goat, dog, cat, mouse, rat, guinea pig, or a transgenic thereof. Includes species.

As used herein, the term “effective” means suitable to achieve a desired, expected, or intended result, as the term is used in the specification and/or claims. “Effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” when used in the context of treating a patient or subject with a compound, when the compound is administered to a subject, individual, or patient to treat or prevent a disease. means the amount of a compound that is sufficient to bring about such treatment or prevention of.

As used herein, the term "pharmaceutically acceptable" refers to human and animal tissues, organs, and tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction, or other problems or complications proportional to a reasonable benefit/risk ratio. /Or refers to a form suitable for use in contact with body fluids.

Another aspect of work is

Step (1) of dissolving trimadol free base to obtain a dissolved product; and

Obtaining a solid reactant by adding felubiprofen to the melt (2); It provides a method for producing ion-binding compounds of felubiprofen and tramadol, including.

In one embodiment, the trimadol free base in step (1) may be obtained by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, which is washed, dried, and filtered. For example, the organic layer of the trimadol free base may be washed with an aqueous sodium chloride solution and dried by removing water using sodium sulfate.

In one embodiment, the free base of trimadol in step (1) may be trans, cis, or a racemic mixture thereof.

In one embodiment, in step (1), the trimadol free base can be obtained in the form of an oily solution.

In one embodiment, the solid reactant in step (2) may be added, mixed, filtered, and dried with felubiprofen divided into fractions in an organic solvent solution of trimadol free base.

In one embodiment, the organic solvent may be methyl t-butyl ether, di-ethyl ether, toluene, dichloromethane, or ethyl acetate, and preferably may be methyl t-butyl ether.

In one embodiment, the production method may further include the step of extracting the tramadol hydrochloride solution with an organic solvent to obtain an organic layer and washing, drying, and filtering the tramadol hydrochloride solution to obtain trimadol free base prior to step (1).

In one embodiment, the tramadol hydrochloride solution may be obtained by adding and mixing an organic solvent and sodium hydroxide to an aqueous solution of tramadol hydrochloride.

In one embodiment, the organic solvent may be methyl t-butyl ether, di-ethyl ether, toluene, dichloromethane, or ethyl acetate, and preferably may be methyl t-butyl ether.

The ionic compound of felubiprofen and tramadol prepared as a result not only exhibits a pain suppressing effect as a substance combining two pharmacologically active ingredients, but is also more effective than a physical mixture of the two ingredients, such as a simple mixture of felubiprofen and tramadol hydrochloride. It is more useful as a pharmaceutical raw material because it can exhibit improved physicochemical properties in terms of property stability, generation of related substances, and solubility. In addition, compared to manufacturing two types of drug substances with different physicochemical characteristics into one tablet, it also provides an economic advantage in that the process of formulating a single compound is overall simple and easy.

The process described above is only an example according to the present invention, and in the present invention, some of each step may be omitted or performed repeatedly, and in some cases, the order of each step may be appropriately changed.

As used herein, terms such as “have,” “may have,” “includes,” or “may include” indicate the presence of the corresponding feature (e.g., numerical value, or component such as an ingredient). indicates, does not rule out the presence of additional features.

The form of the term “comprising” as used herein does not limit the invention to the exclusion of any modifications or additions. Additionally, although the invention has been described in terms of “comprising,” the methods, materials, and compositions described herein may also be described as “consisting essentially of” or “consisting of.”

As used herein, the singular forms “a,” “an,” and “the” can mean one or more, and when a word is used with “comprising,” the word can mean one or more.

Use of the term “or” herein may include “and/or” unless explicitly indicated to refer to alternatives only, or unless the alternatives are mutually exclusive.

The numerical range indicated using the term “to” used in this specification includes the range indicated as the lower limit and upper limit, respectively, with the numerical values written before and after the term “to”.

Additionally, those skilled in the art will understand that variations in numerical quantities are possible. Therefore, whenever a numerical value is mentioned in the specification or claims, it is understood that such numerical value or additional values approximately related to such numerical value are also within the scope of the present invention. Therefore, the numerical values described in this specification are considered to include the meaning of “about” even if not specified. The term "about" or "approximately" means that the referenced value may vary to some extent. For example, the value can vary by 10%, 5%, 2%, or 1%. For example, “about 5” means including any value between 4.5 and 5.5, between 4.75 and 5.25, or between 4.9 and 5.1, or between 4.95 and 5.05.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

[Example]

Hereinafter, the present invention will be explained in more detail by the following examples. However, the following examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Example 1. Preparation of ionic compound of felubiprofen and tramadol

(1) Preparation of tramadol free base

250 g of tramadol hydrochloride was placed in a 3000 mL round bottom flask, dissolved in 1000 mL of water, then 1000 mL of methyl t-butyl ether and 100 mL of 10N NaOH were added, and stirred for 30 minutes. Afterwards, extraction was performed with methyl t-butyl ether to obtain an organic layer, which was washed with saturated aqueous sodium chloride solution. Then, water was removed using sodium sulfate, filtered, and the organic layer was concentrated to obtain 215 g (98%) of tramadol free base as an oily solution.

^1H NMR (METHANOL-d ₄ ) δ: 7.23 (t, J = 8.0 Hz, 1H), 7.08 (br s, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.76 (ddd, J = 8.25) , 2.75, 1.0 Hz, 1H), 3.79 (s, 3H), 2.30 (dd, J = 12.5, 8.5 Hz, 1H), 2.01 (s, 6H), 1.94-1.89 (m, 1H), 1.86-1.82 ( m, 3H), 1.80-1.76 (m, 2H), 1.73-1.68 (m, 1H), 1.66-1.64 (m, 1H), 1.58-1.56 (m, 1H), 1.47-1.42 (m, 1H)

(2) Preparation of ionic compounds of felubiprofen and tramadol

215 g of tramadol free base was dissolved in 1000 mL of methyl t-butyl ether, and 189 g of felubiprofen was added in portions and stirred for 16 hours. Afterwards, the obtained solid was filtered and dried in an oven (65°C, 16 hours) to obtain 210 g of the ion-binding compound of felubiprofen and tramadol (yield 96%).

¹ H NMR (METHANOL-d ₄ ) δ: 7.44 (br s, 1H), 7.39 (dd, J = 13.0, 8.0 Hz, 4H), 7.28 (t, J = 8.0 Hz, 1H), 7.10 (br s, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.81 (dd, J = 8.0, 2.5 Hz, 1H), 3.79 (s, 3H), 3.62 (q, J = 7.0 Hz, 1H), 2.87- 2.82 (m, 3H), 2.51-2.47 (m, 3H), 2.50 (s,6H), 2.18-2.13 (m, 1H), 1.95-1.86 (m, 3H), 1.83-1.74 (m, 5H), 1.71-1.64 (m, 2H), 1.60-1.58 (m, 1H), 1.50-1.45 (m, 1H), 1.43 (d, J = 7.0 Hz, 3H)

Experimental Example 1. Fourier-transform infrared spectroscopy (FT-IR)

FT-IR analysis of the ion-binding compounds of felubiprofen and tramadol obtained in Example 1 was performed by measuring Fourier transform IR spectra using a Thermo Fischer Scientific IS-10. Fourier transform IR spectra were measured for tramadol free base, tramadol hydrochloride, and felubiprofen using the same method.

Figure 1 shows the results of measuring Fourier transform IR spectra for felubiprofen and the ionic compound of tramadol, tramadol free base, tramadol hydrochloride, and felubiprofen.

As shown in Figure 1, the peak at 1729λ in the IR spectrum of felubiprofen appears to be due to the C=O bond of the carboxyl group of felubiprofen, and the peak at 1030-1230λ in the IR spectrum of tramadol free base appears to be due to the C-N bond of tramadol. It appears to be due to combination. However, in the spectra of felubiprofen and tramadol ionic compounds, it was confirmed that the vibration peak was shifted to 1690λ. It was confirmed that the C=O bond of the COOH functional group of felubiprofen was changed to COO- due to the formation of an ionic bond with tramadol, forming an ionic bond compound of felubiprofen and tramadol.

In addition, as shown in Figure 1, the vibration peak at 1030-1230λ in the spectrum of felubiprofen and tramadol ionic compound was different from that of tramadol free base, confirming that felubiprofen and tramadol ionic compound were formed.

In Figure 1, the absorption bands of the FT-IR spectrum of the ionic compound of felubiprofen and tramadol (1:1) are 3199, 2933, 2858, 1675, 1590, 1501, 1481, 1454, 1436, 1418, 1390, 1331. , 1270, 1254, 1202, 1144, 1115, 1041, 1016, 989, 973, 933, 875, 854, 842, 817, 755, 723 and 702λ.

Experimental Example 2. ¹ H-NMR (nuclear magnetic resonance) spectrum analysis

¹ H-NMR analysis was performed on the felubiprofen and tramadol ionic compounds obtained in Example 1 using ¹ H-NMR Bruker Avance II 500 (500 MHz). ¹ H-NMR analysis was also performed on felubiprofen and tramadol free base using the same method.

The ¹ H-NMR analysis results for felubiprofen and tramadol ion-binding compounds, felubiprofen, and tramadol free base are as follows.

(1) Results of ¹ H-NMR analysis of felubiprofen and tramadol ion-binding compounds of Example 1:

¹ H NMR (METHANOL-d ₄ ) δ: 7.44 (br s, 1H), 7.39 (dd, J = 13.0, 8.0 Hz, 4H), 7.28 (t, J = 8.0 Hz, 1H), 7.10 (br s, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.81 (dd, J = 8.0, 2.5 Hz, 1H), 3.79 (s, 3H), 3.62 (q, J = 7.0 Hz, 1H), 2.87- 2.82 (m, 3H), 2.51-2.47 (m, 3H), 2.50 (s,6H), 2.18-2.13 (m, 1H), 1.95-1.86 (m, 3H), 1.83-1.74 (m, 5H), 1.71-1.64 (m, 2H), 1.60-1.58 (m, 1H), 1.50-1.45 (m, 1H), 1.43 (d, J = 7.0 Hz, 3H)

(2) ¹ H-NMR analysis results of felubiprofen:

¹ H NMR (METHANOL-d ₄ ) δ: 7.43 (t, J = 2.0 Hz, 1H), 7.39 (dd, J = 10.5, 8.0 Hz, 4H), 3.74 (q, J = 7.0 Hz, 1H), 2.84 (td, J = 6.5, 2.5 Hz, 2H), 2.49 (t, J = 7.0 Hz, 2H), 1.94-1.89 (m, 2H), 1.78-1.73 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H)

(3) ¹ H-NMR analysis results of tramadol free base:

^1H NMR (METHANOL-d ₄ ) δ: 7.23 (t, J = 8.0 Hz, 1H), 7.08 (br s, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.76 (ddd, J = 8.25) , 2.75, 1.0 Hz, 1H), 3.79 (s, 3H), 2.30 (dd, J = 12.5, 8.5 Hz, 1H), 2.01 (s, 6H), 1.94-1.89 (m, 1H), 1.86-1.82 ( m, 3H), 1.80-1.76 (m, 2H), 1.73-1.68 (m, 1H), 1.66-1.64 (m, 1H), 1.58-1.56 (m, 1H), 1.47-1.42 (m, 1H)

A peak at 3.74 (q, J = 7.0 Hz, 1H) close to the C=O bond of the carboxyl group of felubiprofen in NMR of felubiprofen and NMe ₂ in tramadol free base NMR It was confirmed that the peak at 2.01 (s, 6H) shifted to 3.62 (q, J = 7.0 Hz, 1H) and 2.50 (s, 6H)) peaks, respectively, in the NMR of the ion-binding compounds of felubiprofen and tramadol. In addition, the formation of the ionic compound felubiprofen and tramadol was confirmed because the NMR results of the ionic compound of felubiprofen and tramadol were different from the NMR results of the mixture of felubiprofen and tramadol hydrochloride.

Comparative Example 1. Preparation of a mixture of felubiprofen and tramadol hydrochloride

1.3 g of felubiprofen and 1.5 g of tramadol hydrochloride were mixed to form a 1:1 mixture of felubiprofen and tramadol hydrochloride.

Experimental Example 3. Property stability test

The property stability of Example 1 and Comparative Example 1 was confirmed. Specifically, the properties of Example 1 and Comparative Example 1 were confirmed under high temperature (80 ± 1°C) and high humidity (90 ± 1%) conditions, respectively, and the results are shown in Figures 2 and 3, respectively.

(1) Comparison of property stability under high temperature conditions

Figure 2 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high temperature (80 ± 1°C) conditions.

As shown in Figure 2, when measured under high temperature conditions (80 ± 1°C), Example 1 showed almost no discoloration until 6 months, but Comparative Example 1 was confirmed to have severe discoloration to dark yellow.

(2) Comparison of property stability under high humidity conditions

Figure 3 shows the results of measuring the property stability of Example 1 and Comparative Example 1 over time under high humidity (90 ± 1%) conditions.

As shown in Figure 3, when measured under high humidity conditions (90 ± 1%), Example 1 showed little change in properties until 6 months, but Comparative Example 1 changed from a solid to a yellowish-white sticky liquid (or a yellowish-white sticky oil ( It was confirmed that the appearance had changed to the form of off-white sticky oil.

Through the above results, it was confirmed that the felubiprofen and tramadol ion-binding compounds of the present invention showed improved property stability under both high temperature and high humidity conditions. The ion-binding compounds of felubiprofen and tramadol of the present invention have excellent characteristics as pharmaceutical raw materials in that they facilitate formulation research for development into pharmaceuticals as their property stability is improved.

Experimental Example 4. Severe stability test

A severe stability test was conducted on Example 1 and Comparative Example 1. Specifically, stability tests were conducted under harsh conditions (80 ± 1°C, 90 ± 1%) and analyzed using high-performance liquid chromatography (HPLC) analysis.

(1) HPLC analysis conditions

Detector: Ultraviolet absorption spectrophotometer (wavelength 220nm)

Column: C18 (4.6

Temperature: 40℃

Flow rate: 0.72mL/min

Injection volume: 20㎕

Mobile phase A: Take 1 mL of phosphoric acid and add water to make 2 L. (1->2000 water)

Mobile phase B: Take 1 mL of phosphoric acid and add acetonitrile (CAN) to make 2 L. (1->2000 acetonitrile)

(2) Sample preparation method and gradient conditions

10 mg of sample was taken and placed in a 10 mL amber volumetric flask, and 10 mL of diluent (mobile phase A + mobile phase B mixed in a 2:3 ratio) was injected and filtered to prepare the sample.

method
time (minutes)	Mobile phase A%	Mobile phase B%
0	67	33
20	67	33
50	28	72
55	28	72
60	67	33
* Post run: 10min

(3) Results of measurement of related substances

The results of measuring impurities according to the severe stability test are shown in Table 2 below.

division		High temperature (80±1℃)			High humidity (90±1%)
		Initiate	1 month	3 months	Initiate	1 month	3 months
Example 1	Related substance A	0.12	0.12	0.12	0.12	0.12	0.11
	Related substances B	-	-	-	-	-	-
	Total related substances	0.15	0.24	0.38	0.15	0.15	0.14
Comparative Example 1	Related substance A	0.13	0.25	0.29	0.13	0.12	0.10
	Related substances B	-	0.07	0.14	-	-	-
	Total related substances	0.19	1.26	3.75	0.19	0.20	0.19

* Related substances A and related substances B are for felubiprofen (value: HPLC area %)

Through the above results, it was confirmed that the ion-binding compound of felubiprofen and tramadol of the present invention was more stable than the mixture of Comparative Example 1.

Experimental Example 5. Solubility test

Solubility according to pH was measured for Example 1, Comparative Example 1, and felubiprofen. 200 mg of each material was weighed and dissolved in pH 1.2 (5 mL), pH 6.8 (5 mL), and purified water (5 mL), stirred, PVDF filtered, and confirmed by HPLC analysis. The HPLC analysis method is the same as in Experimental Example 4.

After creating a calibration curve, the concentration was calculated from the linear function, and the solubility is shown in Table 3 below.

division	Solubility (unit: mg/mL)
Felubiprofen	Purified water	0.092
	pH 1.2	0.061
	pH 6.8	3.92
Comparative Example 1	Purified water	0.173
	pH 1.2	0.083
	pH 6.8	6.222
Example 1	Purified water	8.9
	pH 1.2	0.114
	pH 6.8	3.02

As shown in Table 3, the solubility of Example 1 in purified water was significantly higher than that of Comparative Example 1, and at pH 1.2, it was confirmed to be slightly higher than that of Comparative Example 1.

So far, the present invention has been examined focusing on its preferred embodiments. A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims (6)

1. Ionic compound of felubiprofen and tramadol.
2. The compound according to claim 1, wherein the felubiprofen and tramadol are combined in a molar ratio of 1:1.
3. A pharmaceutical composition for treating pain comprising the ion-binding compound of felubiprofen and tramadol according to claim 1 as an active ingredient.
4. The pharmaceutical composition of claim 3, further comprising one or more pharmaceutically acceptable additives selected from the group consisting of disintegrants, diluents, binders, lubricants, and any combinations thereof.
5. Step (1) of dissolving trimadol free base to obtain a dissolved product; and

   Step (2) of obtaining a solid reactant by adding felubiprofen to the melt; A method for producing the ion-binding compound of felubiprofen and tramadol according to claim 1, comprising a.
6. The method of claim 5, wherein in step (1), trimadol free base is prepared by extracting a solution of tramadol hydrochloride with an organic solvent to obtain an organic layer, which is washed, dried, and filtered.

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